The Caris Molecular Tumor Board (CMTB), powered by Caris Life Sciences®, works one on one with oncologists to obtain interpreatation of molecular findings and therapeutic guidance on difficult-to-treat cases. Read how the CMTB approached a patient diagnosed with stage IV cecal cancer with liver and mesenteric metastases below or click here to view the PDF.
Summary: While the diagnosis of Stage IV colon cancer can be awfully devastating, the revelations of the tumor’s molecular vulnerabilities can offer effective therapeutic opportunities and pave a clear path for the treatment plan to the best outcome. This requires thorough interrogation of the patient’s tumor for a complete landscape of the molecular features and interpretation of the molecular information from a multidisciplinary expert group.
The case presented to the Caris Molecular Tumor Board for review is a 79-year old female patient recently diagnosed with stage IV cecal cancer with liver and mesenteric metastases. The patient had received 2 weeks of chemotherapy (capecitabine) before the CMI testing identified that the tumor doesn’t carry one, but two highly actionable alterations: MSI-H/dMMR with a concurrent TPM3-NTRK1 fusion. While the two alterations suggest two treatment options both supported by level 1 evidence, the question at hand, is how to target them sequentially to deliver the most benefit to the patient.
MSI-H/dMMR: Deficient mismatch repair in colorectal tumors are caused by either germline or somatic changes in a key DNA repair mechanism and the resultant microsatellite instability would lead to a large somatic mutational burden and increased neoantigen production that can be effectively targeted by immune checkpoint inhibitions (ICI). This patient’s tumor displays major microsatellite instability, consistent with the observed loss of MLH1 and PMS2 expression. Since no deleterious mutations in MLH1 and PMS2 are seen, it’s likely that the MSI is the result of somatically acquired MLH1 deficiency due to promoter hypermethylation and that loss of PMS2 is secondary to MLH1 loss as it becomes unstable in the absence of MLH1. As expected, a high tumor mutational burden (25 mt/MB) is also observed.
In pre-treated MSI-H/dMMR mCRC, the use of ICIs or their combinations have shown very promising activity and have become part of treatment routine. In the front line setting, the practice-changing results of KEYNOTE-177 trial presented at ASCO Annual 2020 demonstrated doubling of progression-free survival in MSI-H CRC and 66% decrease of severe toxicities when pembrolizumab monotherapy was given; these exciting results added to the accumulating evidence for frontline use of ICI in mCRC and led to the FDA approval for pembrolizumab use in first line, making ICI the new standard of care for MSI-H mCRC.
TPM3-NTRK1 fusion: Comprehensive RNA sequencing also detected a TPM3-NTRK1 fusion in this tumor. It’s now evident that RNA based sequencing is the optimal assay for fusion detection as some targetable fusions are products of splicing out of introns and RNAseq simplifies the technical requirements for adequate coverage; additionally, detection of fusions at the RNA level provides direct evidence of functional transcriptions.
The tropomyosin receptor kinase (Trk) receptor family members are expressed in human neuronal tissue and are actively involved in neuronal development and protection; in cancer, fusions that involve NTRK gene family members (NTRK1, 2, or 3) are targetable by two FDA approved agents, larotrectinib and entrectinib. NTRK fusions are overall very rare in colorectal cancer, seen in less than 1%; the TPM3-NTRK seen in this tumor, however, is the most frequently observed NTRK fusion in colon cancer. The coiled-coil domain of TPM3 fusion partner is likely responsible for the constitutive dimerization of the Trk A and cause kinase activation. Most of reported NTRK fusion-positive CRC tumors are MSI-H and KRAS/NRAS/BRAF wild type, similar to the current case.
The pooled analyses associated with the cancer-agnostic approval of larotrectinib and entrectinib both included small numbers of colorectal tumors (N=8 and 4, respectively) and reported ORRs (50% &. 25%) in these previously-treated CRC tumors are lower than what’s observed in the overall populations (79% and 57%).
Recommendation: In this case of a newly diagnosed metastatic right-sided colon tumor with dMMR/MSI-H, high TMB and a concurrent TPM3-NTRK1 fusion, the recommendation of the Caris Molecular Tumor Board is to proceed with frontline treatment of an immune checkpoint inhibitor, and to potentially pursue an NTRK inhibitor at progression. Standard options for mCRC including chemotherapy in combination or singly with bevacizumab may also be considered.
The Caris Molecular Tumor Board: Provides oncologists with the opportunity to interact with leading cancer experts from across the country to obtain interpretation of molecular findings and therapeutic guidance for individual patients. This proprietary virtual tumor board platform is an innovative, real-time approach to deciphering complex data and treatment decisions on difficult-to-treat cases. The efficient access to cutting information provided by the Caris Molecular Tumor Board allows oncologists to focus their efforts on what matters most – developing the most informed personalized treatment strategies for their patients.
Please visit www.CarisLifeSciences.com/CMTB to register and submit a case for review.
Joanne Xiu, PhD
Igor Astsaturov, MD, PhD
Michael Korn, MD
Rebecca Feldman, PhD